Activation of T cells is an important aspect of the immune system. T cell activation is required for specific immune responses against infectious agents. T cell activation also plays an important role in tumor immunity and in autoimmune and inflammatory disorders. T cell activation is initiated when T cell antigen receptors (TCR) of T cells recognize their specific antigen (Ag) in the context of major histocompatibility complex (MHC) molecules. Although TCR signal transduction is required for naive T cell activation, TCR activation alone is not sufficient to generate an immune response. A secondary signal, known as costimulation, is needed for optimal activation of naive T cells. In particular, signal transduction through the TCR and CD28, known as a costimulatory receptor, are required for activation of naive T cells. B7-1 (CD80) and B7-2 (CD86), known as costimulatory molecules, are two ligands for CD28. B7-1 and B7-2 are typically expressed on professional antigen-presenting cells (APCs). In addition to binding CD28, B7-1 and B7-2 also bind to the co-stimulatory receptor known as CTLA-4 (CD152) on T cells. Another co-stimulatory receptor found on T cells is ICOS.
B7 molecules mediate both positive and negative signals to T cells by binding to costimulatory receptors on T cells. CD28 is the most extensively studied receptor that accepts a secondary signal from B7-1 (CD80) and B7-2 (CD86, B70) to costimulate naive T cells to full activation in the presence of T cell receptor signaling (Linsley et all, 1990, PNAS USA 87: 5031-5035). On the other hand, CTLA-4, a CD28 homolog expressed on activated T cells and interacting with the same set of ligands, attenuates T cell responses (Krummel et al., 1995, J. Exp. Med. 182: 469-465; Walnus et al., 1994, Immunity 1: 405-413). ICOS, another CD28 homolog, is expressed on activated T cells and costimulates T cell activation upon binding of a distinct ligand B7-H2 (ICOSLG, GL50, B7RP1, CD275, ICOSL, LICOS) (Hutloff et al., 1999, Nature 397: 263-266; Yoshinaga et al., 1999, Nature 402: 827-832). CD28, CTLA-4 and ICOS form a tight gene cluster on human chromosome 2q33 and on mouse chromosome 1, suggesting they originated by gene duplication during evolution (Swallow et al., 1999, Immunity 11: 423-432). Although CD28 and ICOS have distinct ligands, they share significant functional redundancy including their capacity in costimulating growth, survival and differentiation of T cells as well as their requirement for antibody response (Ling et al., 2000, J. Immunol. 164: 1653-1657; Ling et al., 2001, Genomics 78: 155-168; Dong et al., 2001, Nature 409: 97-101; McAdam et al., 2001, Nature 409: 102-105; Tafuri et al., 2001, Nature 409: 105-109; Linterman et al., 2009, Immunity 30: 228-241). Both CD28 and ICOS signals have been shown to costimulate an array of cytokines. However, only CD28 signal induces high level of IL-2, while ICOS preferentially stimulates IL-10 (Hutloff et al., 1999, Nature 397: 263-266).
Modulation of costimulatory molecules and their receptors permits the modulation of various immune functions. Agents that modulate the interaction between costimulatory molecules and their receptors may have beneficial use in a variety of applications, including, e.g., therapeutic and prophylactic uses and vaccinations. The present invention fulfills these and other needs.